Opioid receptor antagonists

ABSTRACT

A compound of the formula (I) wherein the variables X 1 , X 2 , B, D, R 1  to R 7  including R 3′ , p, y, q, and z, are as defined or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixtures thereof, useful for the treatment, prevention or amelioration of obesity and Related Diseases is disclosed.

The present invention is in the field of medicinal chemistry. Theinvention relates specifically to compounds useful as opioidantagonists, methods of treatment, methods of using, and pharmaceuticalcompositions thereof.

BACKGROUND

Three types of opioid receptors, mu, kappa, and delta opioid receptorsare generally reported. Recent evidence points to the interactionsbetween receptor dimer combinations of mu, kappa and/or delta receptors(called heterodimers) as also contributing to opioid activity. Opioidreceptors and their normal regulation or lack thereof, has beenimplicated in disease states including irritable bowel syndrome, nausea,vomiting, pruritic dermatoses, depression, smoking and alcoholaddiction, sexual dysfunction, stroke and trauma in animals. Thereforeit is not surprising that the ability to antagonistically bind opioidreceptors has been shown to produce ameliorative, preventative and/ortreatment effects in animals including humans afflicted with one or moreof these disease states.

More recently, certain antagonists of the opioid receptors have beenfound to increase metabolic energy consumption, and reduction of weightin obese rats while maintaining muscle mass. These findings indicatethat an effective opioid antagonist may be useful in preventing,treating and/or ameliorating the effect of obesity. Considering thepercentage of the population that is obese in Western societies and theindirect costs associated with treating the effects and symptoms ofobesity and Related Diseases, the importance of these findings cannot beoverstated.

Though many opioid antagonists have been disclosed, the search continuesfor alternative and/or improved or more effective antagonists having anoverall benefit to the patient with little or no major side effects.U.S. Pat. No. 4,891,379 disclosed phenylpiperidine opioid antagonistsuseful for the treatment of diabetes and obesity. In particular, U.S.Pat. No. 4,891,379 disclosed the compound LY 255582 represented by thestructure

U.S. Pat. No. 6,140,352 discloses the compound of formula

Formula 1

wherein the variables X₁, X₂, X₃ R₁, R₃, R₄, R₅ and R₆ are as describedtherein, as agonists of the beta adrenergic receptor useful for thetreatment of diabetes and obesity.

PCT application WO 9215304 discloses the compounds of formula I

Compound 1 above, encompasses azacyclic and heterocyclic compounds fortreatment of cerebral ischemia.

Regardless of these and other disclosures of compounds useful as opioidreceptor antagonists, or useful for the treatment of obesity, and/ordiabetes by other mechanisms, or having structures partially close tothe compounds of the present invention there remains an unmet medicalneed for useful, safe, effective and/or alternate treatments orprophylaxis of diseases associated with opioid receptors, particularlyobesity and Related Diseases.

SUMMARY OF THE INVENTION

The present invention provides a compound of the formula (I)

p is 0, 1, or 2;q is 0, 1, 2, or 3;y is 0, 1, or 2; and z is 0, 1, or 2;X₁ and X₂ are each independently is CH, or N;B is O, NRt, S, SO, SO₂, or CH₂;D is OH, CONR⁶R⁷, SO₂NR⁶R⁷, NR⁶COR⁷, or NR⁶R⁷; provided that when B isO, D is not CONR⁶R⁷;R¹ and R² are independently selected from hydrogen, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, phenyl, C₁-C₁₀ alkylaryl, C₄-C₁₀alkylcycloalkane, and (CH₂)_(n)C(O)R⁸; wherein each of the alkyl,alkenyl, and aryl groups are optionally substituted with one to twogroups independently selected from C₁-C₈ alkyl, C₂-C₈ alkenyl, phenyl,C₃-C₈ cycloalkyl, C₁-C₈ alkylaryl, and C(O)C₁-C₈ alkyl; and wherein R¹and R² may optionally combine with each other to form a 4, 5, 6, or7-membered nitrogen-containing heterocycle which nitrogen-containingheterocycle may further have substituents selected from the groupconsisting of oxo, amino, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,phenyl, C₁-C₃ alkylaryl, C(O)C₁-C₈ alkyl, CO(O)C₁-C₈ alkyl, halo, C₁-C₃haloalkyl;R³ and R^(3′) are each independently selected from hydrogen, C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, phenyl, aryl, C₁-C₈alkylcycloalkyl, and C₁-C₈ alkylaryl;R⁴ and R⁵ are each independently selected from hydrogen, C₁-C₈ alkyl,C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₈ alkoxy, halo, C₁-C₈ haloalkyl,phenyl, aryl, C₁-C₈ alkylaryl, (CH₂)_(m)NSO₂C₁-C₈ alkyl,(CH₂)_(m)NSO₂-phenyl, (CH₂)_(m)NSO₂aryl, —C(O)C₁-C₈ alkyl, and—C(O)OC₁-C₈ alkyl; wherein each R⁴ and R⁵ is attached to its respectivering only at carbon atoms; wherein m is 1 or 2; and n is 1, 2, or 3;R⁶ and R⁷ are each independently selected from hydrogen, C₁-C₈ alkyl,C₂-C₈ alkenyl, C₂-C₈ alkynyl, C(O)C₁-C₈ alkyl, aryl, C₁-C₈ alkylaryl,C₃-C₇ cycloalkane, C₁-C₆ alkylcycloalkane, (CH₂)_(m)C(O)OR⁸, and(CH₂)_(m)NSO₂R⁸; wherein each of the alkyl, alkenyl, and aryl groups areoptionally substituted with one to two groups independently selectedfrom C₁-C₈ alkyl, C₂-C₈ alkenyl, phenyl, and C₁-C₈ alkylaryl; andwherein when D is NR⁶R⁷ or SO₂NR⁶R⁷, the R⁶ and R⁷ groups mayindependently combine with each other, and with the nitrogen atom towhich they are attached to form a 4, 5, 6, or 7-membered nitrogencontaining heterocycle which nitrogen containing heterocycle mayoptionally have substituents selected from the group consisting of oxo,amino, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, phenyl, and C₁-C₈alkylaryl;R^(t) is selected from the group consisting of hydrogen, C₁-C₈ alkyl,C₂-C₈ alkenyl, C₂-C₈ alkynyl, phenyl, and C₁-C₈ alkylaryl;R⁸ is independently selected from hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl,phenyl, benzyl, and C₅-C₈ alkylaryl;or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer,racemate, diastereomer, or mixture of diastereomers thereof.

The present invention also provides a method for the prevention,treatment and/or amelioration of the symptoms of obesity and RelatedDiseases comprising administering a therapeutically effective amount ofa compound of formula (I) or a pharmaceutically acceptable salt,solvate, enantiomer, racemate, diastereomer or mixture of diastereomersthereof.

The present invention also provides a pharmaceutical formulationcomprising a compound of formula I in association with a carrier,diluent and/or excipient.

The present invention also relates to a method for the treatment and/orprophylaxis of obesity and Related Diseases including eating disorders(bulimia, anorexia nervosa, etc, diabetes, diabetic complications,diabetic retinopathy, sexual/reproductive disorders, depression,anxiety, epileptic seizure, hypertension, cerebral hemorrhage,congestive heart failure, sleeping disorders, atherosclerosis,rheumatoid arthritis, stroke, hyperlipidemia, hypertriglycemia,hyperglycemia, hyperlipoproteinemia, substance abuse, drug overdose,compulsive behavior disorders (such as paw licking in dog), andaddictive behaviors such as for example, gambling, and alcoholism,comprising administering a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt, solvate,enantiomer, racemate, diastereomer or mixture of diastereomers thereof.

The present invention relates to a compound of formula (I) useful forthe manufacture of a medicament for the treatment, prevention and/oramelioration of symptoms associated with obesity and Related Diseases.

In another embodiment, the present invention relates to a compound offormula I or a pharmaceutically acceptable salt, solvate, enantiomer,racemate, diastereomer or mixture thereof, useful as an appetitesuppressant.

The present invention relates to a method of achieving weight loss whilemaintaining lean muscle mass or minimizing the loss of lean muscle masscomprising administering a compound of formula I or a pharmaceuticallyacceptable salt, solvate, enantiomer, racemate, diastereomer or mixturethereof, to a patient in need thereof.

The present invention provides a compound of formula I useful singly orin combination with other agents approved for the treatment, preventionand/or amelioration of obesity and related diseases and symptomsthereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “patient” includes human and non-human animalssuch as companion animals (dogs and cats and the like) and livestockanimals.

The preferred patient of treatment, amelioration and/or prevention ofobesity and Related Diseases is a human.

The terms “treating” and “treat”, as used herein, include theirgenerally accepted meanings e.g. preventing, prohibiting, restraining,alleviating, ameliorating, slowing, stopping, or reversing theprogression or severity of a pathological condition, or sequela thereof,described herein.

The terms “ameliorating” “preventing”, “prevention of”, “prophylaxis”,“prophylactic” and “prevent” are used herein interchangeably and referto reducing the severity of obesity and Related Diseases and thesymptoms associated therewith, in a patient afflicted with same orreducing the likelihood that the recipient of a compound of formula Iwill be afflicted with or develop any of the pathological conditions orsequela thereof described herein.

As used herein, the term “effective amount” is synonymous with“effective dose” and means an amount of a compound of formula I that issufficient in one or more administrations for preventing, amelioratingor treating a condition, or detrimental effects thereof, hereindescribed, or an amount of a compound of formula I that is sufficientfor antagonizing the opioid receptors to achieve the objectives of theinvention.

The term “pharmaceutically acceptable” is used herein as an adjectiveand means substantially non-deleterious to the recipient patient.

The term “Active Ingredient” as used herein means a compound of formulaI or a combination of a compounds of formula I or a combination of acompound of formula I and a co-antagonist of the opioid receptor or acombination a compound of formula I and other effective anti-obesity,weight loss or antidiabetic agent.

The term “formulation”, as in pharmaceutical formulation, or“pharmaceutical composition” is intended to encompass a productcomprising the Active Ingredient (as defined supra), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical formulations of the present invention encompass anyeffective composition made by admixing a compound of the presentinvention and a pharmaceutical carrier. The pharmaceutical formulationsof the present invention also encompass a compound of the formula I anda pharmaceutically acceptable co-antagonist of opioid receptors usefulfor the treatment and/or prevention of obesity or Related Diseases.

The term “Related Diseases” as used herein refers to such symptoms,diseases or conditions caused by, exacerbated by, induced by or adjunctto the condition of being obese. Such diseases, conditions and/orsymptoms include but are not limited to eating disorders (bulimia,anorexia nervosa, etc.), diabetes, diabetic complications, diabeticretinopathy, sexual/reproductive disorders, depression (particularlythat induced by the awareness and loss of self esteem associated withobesity), anxiety, epileptic seizure, hypertension, cerebral hemorrhage,congestive heart failure, sleeping disorders, atherosclerosis,rheumatoid arthritis, stroke, hyperlipidemia, hypertriglycemia,hyperglycemia, and hyperlipoproteinemia.

As used herein “other agents” approved for the treatment of obesityand/or related disease, or useful for weight loss and/or appetitesuppression include but are not limited to Xenical®, Meridia®, Lipitor®,Crestor®, Pravachol®, Zetia®, cannabinoid receptor antagonists, andother opioid receptor antagonists.

The term “suitable solvent” refers to any solvent, or mixture ofsolvents, inert to the ongoing reaction that sufficiently solubilizesthe reactants to afford a medium within which to effect the desiredreaction.

The term “mutual solvent” means a solvent that is used to dissolvesufficiently, two or more components of a reaction or mixture separatelyprior to reaction or mixing, that is a solvent common to more than onereagents or components of a mixture.

The term “nitrogen containing heterocycle” refers to a monocycle whichis a 4, 5, 6, or 7-member ring containing 1, 2 or 3 nitrogen atoms inaddition to the carbon atoms completing the ring size, or a combinationof 1 nitrogen atom and 1, or 2 atoms selected from oxygen, and sulfur inaddition to the appropriate number of carbon atoms completing the ringsize. A nitrogen containing heterocycle as used here may have 0, 1, 2 or3 double bonds. A nitrogen containing heterocycle may be attached to orfused to an existing ring substituent thus forming a bicyclic ortricylic ring system. Nonetheless, the direct result of the formation ofa nitrogen containing heterocycle by the joining of two groups and thenitrogen atom to which they are attached is to form a monocycle.

The term “C₁-C₈ alkyl” or C₁₋₈ alkyl” refers to and includes all groups,structural isomers and for homologues of alkyl groups having from 1 to 8carbon atoms. When the term C₁-C₈ alkyl precedes or prefixes anothergroup, the term C₁-C₈ alkyl, only limits the number of carbon atoms inthe alkyl component. For example C₁-C₈ alkyaryl means an aryl grouphaving a C₁-C₈ alkyl group substituent such that the number of carbonatoms in the group C₁-C₈ alkylaryl is effectively the number of carbonatoms in the aryl group plus the number of carbon atoms in the C₁-C₈alkyl group. Similarly, the term “C₁-C₈ alkylcycloalkyl” refers to acycloalkane group having a C₁-C₈ alkyl substituent, and wherein theentire group C₁-C₈ alkylcycloalkane may itself be a substituent attachedat either the alkyl group or the cycloalkyl group to a substrate. Thedefinition and usage applies equally to other homologues of C₁-C₈ suchas for example, C₁-C₇, C₁-C₆ etc.

The term “cycloalkane” or “cycloalkyl’ means cycloalkanes having from 3to 8 carbon atoms i.e. from cyclopropane to cyclooctane.

The term “hal” or “halo” as used herein refers to a halogen includingfluorine, chlorine, bromine or iodine.

As used herein the terms “alkenyl” refers to straight or branched carbonatoms having 1 or 2 carbon-carbon double bonds.

As used herein the terms “alkynyl” refers to straight or branched carbonatoms having 1 or 2 carbon-carbon triple bonds.

As used herein the term “alkoxy” refers to the group “O-alkyl” whereinalkyl is as defined previously.

The term “aryl” as used herein refers to compounds or groups having theHuckel 4n+2 pi electron arrangement and includes phenyl, benzyl,naphthyl, but excludes carbazoles and other fused tricyclic ringstructures.

It is understood by one of skill in the art that where a substituent isabsent, a hydrogen atom is indicated to achieve the required valencyunless otherwise indicated. For example, if y is o, then R⁴ is absent,and all applicable positions on the ring have hydrogen atoms to achievethe required valency for atoms in the ring.

As used herein, the term “protecting group” refers to a groups usefulfor masking reactive sites in a molecule to enhance the reactivity ofanother group or allow reaction at another desired site or sitesfollowing which the protecting group may be removed. Protecting groupsare usually used to protect or mask groups including but not limited to—OH, —NH, and —COOH. Suitable protecting groups are known to one ofskill in the art and are described in Protecting groups in OrganicSynthesis, 3^(rd) edition, Greene, T. W.; Wuts, P. G. M. Eds.; JohnWiley and Sons, New York, 1999.

As used herein, the term “solvate” is a form of the compound of theinvention wherein a crystal or crystals of a compound of the inventionhave been formed from a stoichiometric or non-stoichiometric amount ofthe compound of formula I and a solvent. Typical solvating solventsinclude for example, water, methanol, ethanol, acetone anddimethylformamide.

In those instances where a compound of the invention possesses acidic orbasic functional groups, various salts may be formed which are morewater soluble and/or more physiologically suitable than the parentcompound. Representative pharmaceutically acceptable salts, include butare not limited to, the alkali and alkaline earth salts such as lithium,sodium, potassium, calcium, magnesium, aluminum and the like. Salts areconveniently prepared from the free acid by treating the acid insolution with a base or by exposing the acid to an ion-exchange resin.

Included within the definition of pharmaceutically acceptable salts arethe relatively non-toxic, inorganic and organic base addition salts ofcompounds of the present invention, for example, ammonium, quaternaryammonium, and amine cations, derived from nitrogenous bases ofsufficient basicity to form salts with the compounds of this invention(see, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Phar.Sci., 66: 1-19 (1977)). Moreover, the basic group(s) of the compound ofthe invention may be reacted with suitable organic or inorganic acids toform salts such as acetate, benzenesulfonate, benzoate, bicarbonate,bisulfate, bitartrate, borate, hydrobromide, camsylate, carbonate,clavulanate, citrate, chloride, edetate, edisylate, estolate, esylate,fluoride, fumarate, gluceptate, gluconate, glutamate,glycolylarsanilate, hexylresorcinate, hydrochloride, hydroxynaphthoate,hydroiodide, isothionate, lactate, lactobionate, laurate, malate,maleate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, sulfite, sulfate, mucate, napsylate, nitrate, oleate,oxalate, palmitate, pantothenate, phosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, tannate, tartrate,tosylate, trifluoroacetate, trifluoromethane sulfonate, and valerate.

A compound of the invention as illustrated by formula I may occur as anyone of its positional isomers, stereochemical isomers or regio-isomers,all of which are objects of the invention. Certain compounds of theinvention may possess one or more chiral centers, and thus, may exist inoptically active forms. Likewise, when the compounds contain an alkenylor alkenylene group, there exist the possibility of cis- andtrans-isomeric forms of the compounds. The R- and S-isomers and mixturesthereof, including racemic mixtures as well as mixtures of enantiomersor cis- and trans-isomers, are contemplated by this invention.Additional asymmetric carbon atoms can be present in a substituent groupsuch as an alkyl group. All such isomers as well as the mixtures thereofare intended to be included in the invention. If a particularstereoisomer is desired, it can be prepared by methods well known in theart by using stereospecific reactions with starting materials whichcontain the asymmetric centers and are already resolved or,alternatively by methods which lead to mixtures of the stereoisomers andsubsequent resolution by known methods. For example, a racemic mixturemay be reacted with a single enantiomer of some other compound i.e. achiral resolving agent. This changes the racemic form into a mixture ofstereoisomers and diastereomers, because they have different meltingpoints, different boiling points, and different solubilities and can beseparated by conventional means, such as crystallization.

The compounds of the present invention have shown inhibition oforexigenic effects, and are thus useful as appetite suppressants eitheras a single therapy or in conjunction with exercise and other effectiveappetite suppressing or weight loss medications.

PREFERRED EMBODIMENTS OF THE INVENTION

A compound of formula I preferably exists as the free base or apharmaceutically acceptable salt. More preferred is the hydrochloridesalt, the bisulfate salt, mesylate or the oxalic acid salt of thecompound of formula I.

For the groups R¹ and R²

Preferred R¹ and R² groups are independently selected from the groupconsisting of hydrogen, methyl, ethyl, propyl, pentyl, and isopropyl.Also preferred are R¹ and R² groups independently selected from thegroup consisting of methyl, ethyl, propyl, isopropyl, phenyl,

each of which is optionally substituted with a group selected from thegroup consisting of halogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₁-C₈thioalkyl, C₁-C₈ alkylamino, phenyl, C₁-C₈ alkylsubstituted phenyl,C₄-C₈ heterocycle or C₁-C₄ alkyl heterocycle; or combine with a groupselected from C₁-C₈ alkyl, halogen, C₁-C₈ haloalkyl, C₁-C₈ thioalkyl,C₁-C₈ alkylamino, phenyl, C₁-C₈ alkylsubstituted phenyl, C₄-C₈heterocycle or C₁-C₄ alkyl heterocycle to form a substituted orunsubstituted bicycle or tricycle.

Also preferred are R¹ and R² groups that combine with each other to forma group selected from the group consisting of

each of which is optionally substituted with a group selected from thegroup consisting of halogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₁-C₈thioalkyl, C₁-C₈ alkylamino, phenyl, C₁-C₈ alkylsubstituted phenyl,C₄-C₈ heterocycle or C₁-C₄ alkylheterocycle.Preferred R³ and R^(3′) Groups

A preferred R³ is hydrogen. A preferred R^(3′) group is selected fromhydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl andbenzyl. More preferably, both R³ and R^(3′) are hydrogen.

Preferred R⁴ Groups

A preferred R⁴ group is selected from the group consisting of hydrogen,halo, C₁-C₅ alkyl, C₁-C₅ haloalkyl, C₁-C₅ alkoxy, C₁-C₅ alkylamino,phenyl, C₁-C₅ alkylphenyl, C1-C5 alkylcycloalkyl, and C₁-C₅ thioalkyl.More preferred is a R⁴ group selected from the group consisting ofhydrogen, methyl, ethyl, isopropyl, chloro, fluoro, trifluoromethyl,methoxy, ethoxy, thiomethyl, phenyl, and benzyl. Most preferred is an R⁴group selected from the group consisting of hydrogen, methyl, ethyl,isopropyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, propoxy,isopropoxy, and benzyl.

Though the groups R⁴ and a R⁵ may exist as multiple substituents ontheir respective ring substrates, a preferred embodiment of theinvention involves compounds wherein each of R⁴, and R⁵ areindependently absent, or singly substituted on their respective ringsubstrates.

Preferred R⁵ Groups

A preferred R⁵ group is selected from the group consisting of hydrogen,halo, C₁-C₅ alkyl, C₁-C₅ haloalkyl, C₁-C₅ alkoxy, C₁-C₅ alkylamino,phenyl, C₁-C₅ alkylphenyl, C1-C5 alkylcycloalkyl, and C₁-C₅ thioalkyl.More preferred is an R⁵ group selected from the group consisting ofhydrogen, methyl, ethyl, isopropyl, chloro, fluoro, trifluoromethyl,methoxy, ethoxy, thiomethyl, phenyl, and benzyl. A most preferred R⁵group is selected from the group consisting of hydrogen, methyl, ethyl,isopropyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, and benzyl.

Preferred R⁶ and R⁷ Groups

Preferred are R⁶ and R⁷ groups independently selected from the groupconsisting of hydrogen, methyl, ethyl, propyl, pentyl, isopropyl, phenyland benzyl.

Also preferred are compounds of formula I wherein R⁶ and R⁷independently combine with each other, and with the nitrogen atom towhich they are attached to form a 4, 5, 6, or 7-membered nitrogencontaining heterocycle which nitrogen containing heterocycle optionallyhas substituents selected from the group consisting of oxo, amino, C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, phenyl, C₁-C₈ alkylaryl, C(O)C₁-C₈alkyl, CO(O)C₁-C₈ alkyl, hydroxy, C₁-C₈ alkoxy, halo, and haloalkyl.Most preferred are compounds of the invention wherein R⁶ and R⁷ are bothhydrogen.

Preferred values for n, m, and p, y, z

A preferred value for n is 0, 1 or 2.

A preferred value for m is 1 or 2.

A preferred value for p is 0, 1, or 2. More preferred is p=1.

A preferred value for y is 0, or 1

A preferred value for z is 0, or 1.

A preferred compound according to the present invention is a compoundselected from the group consisting of:

-   4-[4-(2-Methylamino-ethyl)-phenoxy]-phenol,-   4-{4-[2-(Benzyl-methyl-amino)-ethyl]phenoxy}-phenol,-   Acetic acid 4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl ester,-   6-[4-(Benzylamino-methyl)-phenylsulfanyl]-nicotinamide,-   6-{4-[(3-Methyl-butylamino)-methyl]-phenylsulfanyl}-nicotinamide,-   6-{4-[(2-Pyridin-4-yl-ethylamino)-methyl]-phenylsulfanyl}-nicotinamide,-   6-[4-(Phenethylamino-methyl)-phenylsulfanyl]-nicotinamide,-   6-{4-[(Cyclopropylmethyl-amino)-methyl]-phenylsulfanyl}-nicotinamide,-   6-{4-[(2-Thiophen-2-yl-ethylamino)-methyl]-phenylsulfanyl}-nicotinamide,-   6-{4-[(3-Phenyl-propylamino)-methyl]-phenylsulfanyl}-nicotinamide,-   6-{4-[(3-Methyl-butylamino)-methyl]-phenylsulfanyl}-nicotinamide,-   4-[4-(Phenethylamino-methyl)-benzenesulfonyl]-benzamide,-   4-[4-(Phenethylamino-methyl)-benzenesulfinyl]-benzamide,-   6-[4-(2-Benzylamino-ethyl)-phenylamino]-nicotinamide,-   6-{4-[2-(Cyclohexylmethyl-amino)-ethyl]-phenylamino}-nicotinamide,-   6-{4-[(2-Pyridin-4-yl-ethylamino)-methyl]-phenylsulfanyl}-nicotinamide,-   6-[4-(Benzylamino-methyl)-phenylamino]-nicotinamide,-   6-{4-[(Cyclohexylmethyl-amino)-methyl]-phenylamino}-nicotinamide,-   6-[4-(Phenethylamino-methyl)-phenylamino]-nicotinamide,-   6-{4-[(3-Methyl-butylamino)-methyl]-phenylamino}-nicotinamide,-   N-{4-[4-(2-Benzylamino-ethyl)-phenoxy]-phenyl}-acetamide,-   N-{4-[4-(2-Hexylamino-ethyl)-phenoxy]-phenyl}-acetamide,-   N-[4-(4-{2-[(Thiophen-2-ylmethyl)-amino]-ethyl}-phenoxy)-phenyl]-acetamide,-   N-(4-{4-[2-(3-Phenyl-propylamino)-ethyl]-phenoxy}-phenyl)-acetamide,-   N-(4-{4-[2-(2-Cyclohexyl-ethylamino)-ethyl]phenoxy}-phenyl)-acetamide,-   N-{4-[4-(2-Phenethylamino-ethyl)-phenoxy]-phenyl}-acetamide,-   N-{4-[4-(2-Propylamino-ethyl)-phenoxy]-phenyl}-acetamide,-   N-{4-[4-(2-Pentylamino-ethyl)-phenoxy]-phenyl}-acetamide,-   N-(4-{4-[2-(Cyclohexylmethyl-amino)-ethyl]-phenoxy}-phenyl)-acetamide,-   N-(4-{4-[2-(2-Trifluoromethyl-benzylamino)-ethyl]-phenoxy}-phenyl)-acetamide,-   N-[4-(4-{2-[(Furan-2-ylmethyl)-amino]-ethyl}-phenoxy)-phenyl]-acetamide,-   N-(4-{4-[2-(3-Chloro-benzylamino)-ethyl]-phenoxy}-phenyl)-acetamide,-   4-[4-(2-Benzylamino-ethyl)-phenoxy]-phenylamine,-   N-{4-[4-(2-Benzylamino-ethyl)-phenoxy]-phenyl}-benzamide,-   Morpholine-4-carboxylic acid    {4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-amide,-   N-{4-[4-(2-Benzylamino-ethyl)-phenoxy]-phenyl}-2-methoxy-acetamide,-   Furan-2-carboxylic acid    {4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-amide,-   Isoxazole-5-carboxylic acid    {4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-amide,-   Thiophene-2-carboxylic acid    {4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-amide,-   N-{4-[4-(2-Benzylamino-ethyl)-phenoxy]-phenyl}-isonicotinamide,-   3,5-Dimethyl-isoxazole-4-carboxylic acid    {4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-amide,-   2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid    {4-[4-(2-benzylamino-ethyl)-phenoxyl]-phenyl}-amide,-   5-Methyl-isoxazole-3-carboxylic acid    {4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-amide,-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    {4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-amide,-   N-{4-[4-(2-Benzylamino-ethyl)-phenoxy]-phenyl}-3-methylsulfanyl-propionamide,-   Quinoxaline-2-carboxylic acid    {4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-amide,-   N-{4-[4-(2-Benzylamino-ethyl)-phenoxy]-phenyl}-nicotinamide,-   Pyridine-2-carboxylic acid    {4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-amide,-   N-(6-{4-[(3-Methyl-butylamino)-methyl]-phenoxy}-pyridin-3-yl)-acetamide,    or a pharmaceutically acceptable salt, solvate, enantiomer,    diastereomer and diastereomeric mixture thereof.

Preparing Compounds of the Invention

Compounds of formula I may be prepared as described in the followingschemes and/or examples or following a combination of schemes know toone of skill in the art for making fragments and combinations thereof.Compounds employed as initial starting materials in the synthesis ofcompounds of the invention are well known and, to the extent notcommercially available, are readily synthesized using specificreferences provided, or by standard procedures commonly employed bythose of ordinary skill in the art and/or found in general referencetexts.

More particularly, the compounds of the invention are produced inaccordance with schemes 1 through 3 that are described in detail below,or analogous methods thereto. These reactions are often carried outfollowing known procedures, methods, or analogous methods thereto.Examples of such known procedures and/or methods include those describedin general reference texts such as Comprehensive OrganicTransformations, VCH Publishers Inc, 1989; Compendium of OrganicSynthetic Methods, Volumes 1-10, 1974-2002, Wiley Interscience; AdvancedOrganic Chemistry, Reactions Mechanisms, and Structure, 5^(th) Edition,Michael B. Smith and Jerry March, Wiley Interscience, 2001; AdvancedOrganic Chemistry, 4^(th) Edition, Part B, Reactions and Synthesis,Francis A. Carey and Richard J. Sundberg, Kluwer Academic/PlenumPublishers, 2000, etc., and references cited therein.

Compounds of the invention may be prepared following the proceduresdiscussed in the schemes below, the experimental section or followingknown variations of same. Scheme I for example shown the preparation ofcompounds of formula I wherein B is O, and D is other than CONR⁶R⁷.

According to scheme 1, ethyl chloroformate is added to a solution oftyramine (1), sodium hydroxide, and water to produce the[2-(4-hydroxy-phenyl)-ethyl]carbamic acid ethyl ester (2). The carbamateis treated with cesium carbonate and 4-fluorobenzonitrile in DMF toyield the corresponding biarylether 3. The nitrile functionality of thebiaryl; ether 3 is converted to the N-acyl compound 4 by reaction withmethyllithium followed by hydrolysis in aqueous sulfuric acid. TheN-acyl compound 4 is converted to the acetate 5 by oxidation withm-chloroperbenzoic acid (MCPBA) in a suitable solvent. The acetate 5 isreduced with lithium aluminum hydride to afford the compound4-[4-(2-methylamino-ethyl)-phenoxy]-phenol (6). The compound 6 istreated with benzaldehyde in the presence of sodiumtriacetoxyborohydride to produce the reductive amination product4-{4-[2-(benzyl-methyl-amino)-ethyl]-phenoxy}-phenol 7 of formula I.Compounds of formula I wherein D is acetate and q is 0, may also beprepared according to scheme 2 below.

According to Scheme 2, tyramine is treated with benzaldehyde in sodiumborohydride, molecular sieves, and methanol to produce the reductiveamination product 4-(benzylamino-ethyl)-phenol (8). The phenol 8 istreated with cesium carbonate and 4-fluorobenzonitrile in DMF to yieldthe corresponding biarylether 9. The nitrile functionality of the biarylether may be converted to the acetate 10 with methyl lithium followed byhydrolysis in aqueous sulfuric acid. The acetate 10 is oxidized withMCPBA to yield acetic acid 4-[4-(2-benzylamino-ethyl)-phenoxy]-phenylester (11).

Compounds of the invention wherein B is S, SO or SO₂ may be preparedfollowing the procedure of scheme 3 and for modifications thereof.

According to scheme 3,4-(Methylthio)benzaldehyde (12) or analog thereof,is demethylated with 2-methyl-2-propanethiol sodium salt to yield the4-mercapto-benzaldehyde 13. The thiol product 13 is treated withpotassium carbonate and 6-chloro-nicotinamide or other halonicotinamideor halobanzamide in DMF to afford the corresponding biarylthioether 14.Reductive amination of the biarylthiother 14 with a desired amine in thepresence of sodium borohydride, molecular sieves, and methanol affordsupon workup and isolation the carboxamide compound 15. Oxidativeconditions were employed to produce the corresponding sulfoxide andsulfone. For example, ozonlolysis of compound 15 affords the sulfone 16,while oxidation using sodium periodate affords the sulfoxide 17, bothcompounds of formula 1.

Compounds of the invention wherein B is NH may be prepared following theprotocol of Scheme 4.

As shown in Scheme 4, the desired aminonitrile e.g. 4-amino benzonitrile(18) is combined with 6-chloro-nicotinamide at about 150° C. to producethe phenylaminonicotinamide (19). The nitrile 19 is catalyticallyreduced using procedures known to one of skill in the art such as forexample, 5-10% palladium on carbon with or without other co-catalysts toafford the primary amine (20). Alternatively, an amino nicotinonitrilemay be reacted with an appropriately substituted halobenzamide orhalonicotinamide to afford the corresponding coupled nitrile product(analog of 20). The coupled nitrile product 19 or analog thereof is thenreduced as discussed above to afford the corresponding primary amine 20or analog thereof. The primary amine 20 is treated with the appropriatealdehyde under reductive amination conditions using sodium borohydride,molecular sieves, and methanol, to produce the desired compound offormula I, e.g. compound 21.

Compounds of formula I where D is a reverse amide (NR⁶COR⁷) may beprepared following the protocol of Scheme 5.

As shown in scheme 5, tyramine is protected as the t-butyl carbamate 22and then reacted with 4-fluoronitrobenzene with cesium carbonate in DMFto yield the corresponding biarylether,{2-[4-(4-nitro-phenoxy)-phenyl]ethyl}-carbamic acid tert-butyl ester(19). Compound 19 is reduced by catalytic hydrogenation with palladiumon carbon at the nitro group to afford the amine 23. Compound 23 is thenN-acylated with acetyl chloride to afford the N-acyl compound 25. Thet-Boc protecting group is removed from compound 25 using TFA indichloromethane and the resulting amine 26 is reacted with variousaldehydes under reductive amination conditions to afford compound 27.

Compounds of formula I wherein D is a reverse amide may also be preparedfollowing the protocol of scheme 6

According to scheme 6, tyramine (1) is reacted with benzaldehyde underreductive amination conditions to yield 4-(2-benzylamino-ethyl)-phenol(28). The amine 28 is protected as the t-butyl carbamate (29). Thecarbamate 29 is reacted with 4-fluoronitrobenzene under basic reactionconditions (as shown or known modifications thereof) to afford thecoupled product 30. The coupled product 30 is then reduced at the nitrogroup utilizing catalytic hydrogenation (palladium on carbon) to afford{2-[4-(4-amino-phenoxy)-phenyl]-ethyl}-benzyl-carbamic acid tert-butylester (31). The resulting amine 31 may be acylated with one of variousacid chlorides to form the desired reverse amide compound 32. The Bocprotecting group is removed with TFA in dichloromethane to affordcompound 33, a compound of the invention.

As shown in scheme 7, 4-Hydroxybenzaldehyde is treated with potassiumcarbonate and 2,5-dibromopyridine in DMAC to afford4-(5-bromo-pyridin-2-yloxy)-benzaldehyde (35). The aldehyde 35 iscombined with isoamylamine, sodium triacetoxyborohydride, acetic acid,and dichloromethane to yield the reductive amination product[4-(5-bromo-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-amine (36). Theresulting aryl bromide 36 is treated with acetamide, copper iodide, and1,2 diaminocyclohexane in dioxane to yield the target compound 37.

Though protocols have been provided above for the preparation ofspecific examples one of skill in the art is aware that other compoundsof formula I or analogs of those thought in the protocols ma be preparedfollowing generally the protocols disclosed. For example, optionallysubstituted analogs and isomers of may be prepared using the appropriateanalogs of starting materials including positional isomers andoptionally substituted analogs of starting materials, and intermediates.Similarly, one of skill is aware of suitable solvents, temperatures andother routine reaction conditions in addition to or in place of thosedisclosed that may be necessary to effect improved yields for particularsubstrates or target products.

Method of Using the Invention

As noted above, the compounds of the present invention are useful inblocking the effect of agonists at mu, kappa, and/or delta opioidreceptors. As such, the present invention also provides a method forblocking a mu, kappa, delta receptor or receptor combination(heterodimer) thereof in a mammal comprising administering to saidmammal a receptor blocking dose of a compound of formula I.

The term “receptor blocking dose”, as used herein, means an amount of acompound of formula I necessary to block a mu, kappa, or delta receptoror receptor combination (heterodimer) thereof following administrationto a mammal requiring blocking of a mu, kappa, or delta receptor orreceptor combination (heterodimer) thereof.

The compounds of formula I or combinations thereof, are effective over awide dosage range. For example, dosages per day will normally fallwithin the range of about 0.05 to about 250 mg/kg of body weight. In thetreatment of adult humans, the range of about 0.5 to about 100 mg/kg, insingle or divided doses, is preferred. However, it will be understoodthat the amount of the compound actually administered will be determinedby a physician in light of the relevant circumstances, including thecondition to be treated, the choice of compound to be administered, theage, weight, response of the individual patient, the severity of thepatient's symptoms, and the chosen route of administration. Therefore,the above dosage ranges are not intended to limit the scope of theinvention in any way. The compounds may be administered by a variety ofroutes such as the oral, transdermal, subcutaneous, intranasal,intramuscular and intravenous routes.

A variety of physiologic functions have been shown to be subject to orinfluenced by mu, kappa, or delta receptors or receptor combination(heterodimers) in the brain. As such, the compounds of the presentinvention are believed to have the ability to treat disorders associatedwith these receptors or combinations thereof such as eating' isorders,opioid overdose, depression, smoking, alcoholism, sexual dysfunction,shock, stroke, spinal damage and head trauma. As such, the presentinvention also provides methods of treating the above disorders byblocking the effect of agonists at a mu, kappa, delta receptors orreceptor combinations (heterodimer) thereof.

Assay Methodology

The compounds of the present invention have been found to display usefulactivity in an opioid receptor binding assay which measures the abilityof the compounds to block the mu, kappa, delta or receptor combination(heterodimer) thereof.

The functional antagonist potency (Kb) of the sample compounds wasdetermined using the GTPγS binding assay. GTPgS-based functional assaysprovide an in vitro measure of the activity of opioid agonists andantagonists. Opioid reference compounds or test compound are incubatedwith membrane homogenate from cells expressing the cloned human mu,kappa or delta opioid receptor and radiolabeled [35S]GTPgS. If thecompound activates the opioid receptor, an increase in the binding ofradiolabeled GTPgS is observed. Similarly, if the compound exhibitsantagonist activity, it interferes with the ability of the controlagonist to stimulate GTPgS binding. These tests provide an in vitromeasurement of the activity of the compound at human opioid receptors.GTP-γ-S Binding Assay

An SPA-based GTP-γ-S assay format was developed based on previous opioid(Emmerson et al., J. Pharm Exp Ther 278, 1121, 1996; Horng et al.,Society for Neuroscience Abstracts, 434.6, 2000) and muscarinic (DeLappet al., JPET 289, 946, 1999) assay formats. Membranes were resuspendedin 20 mM HEPES, 100 mM NaCl, 5 mM MgCl₂, 1 mM DTT, and 1 mM EDTA. Fifty(50) mL, of GTP-γ-[35S], compound; membrane suspension (20microgram/well), and wheat germ agglutinin coated SPA beads (1 mg/well)were added to clear bottom 96 well assay plates. GDP (200 mM) was addedto the membrane solution prior to addition to the assay plates. Plateswere sealed and incubated for four hours at room temperature then placedin a refrigerator overnight to allow the beads to settle. Signalstability at 4° C. was determined to be >6O hours. Plates were warmed toroom temperature and counted in a Wallac Microbeta scintillationcounter. For antagonist assays, specific agonists were added at thefollowing concentrations: (MOR) DAMGO 1 micromolar, (DOR) DPDPE 30 nM,(KOR) U69593 300 nM. Kb's were determined by Cheng-Prusoff equation (seeCheng and Prusoff, Biochem. Pharmacol. 22, 3099, 1973). Results obtainedfor a sample of compounds of the invention in the GTP-γ-S Binding Assayare shown in table 1 below.

TABLE 1 Receptor Binding (Ki, nM) Example # Mu Kappa Delta 24 197.9952666.625 4024.180 25 67.475 3971.810 2513.985 27 64.255 618.350 1319.60028 26.905 149.815 469.235 29 5.055 731.050 62.535 27 199.880 >5000 >500030 18.015 163.050 260.150 10 726.185 >5000 3036.670 6 228.725 1616.7403249.040 5 1314.740 >5000 >5000 36 >2500 >4000 >5000 371753.830 >4000 >5000 38 1721.810 >4000 >5000 39 >2500 >4000 >5000 40911.870 >4000 >5000 13 563.465 2435.285 3523.735 14 86.445 1022.330714.465 15 292.470 653.775 1824.015 16 45.395 1018.085 269.740 171347.320 761.245 >5000 18 48.740 466.448 278.380 19 107.185 137.380858.035 20 73.240 402.045 537.255 21 >3000 >4000 >5000 22 >3000 >4000>5000

Formulation

A compound of the invention is preferably presented in the form of apharmaceutical formulation comprising a pharmaceutically acceptablecarrier, diluent or excipient and a compound of the invention. Suchcompositions will contain from about 0.1 percent by weight to about 90.0percent by weight of the compound of the invention (Active Ingredient).As such, the present invention also provides pharmaceutical formulationscomprising a compound of the invention and a pharmaceutically acceptablecarrier, diluent or excipient therefore.

In making the compositions of the present invention, the activeingredient will usually be mixed with a carrier, or diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, semi-solid or liquid material that acts as avehicle, excipient or medium for the active ingredient. Thus, thecomposition can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, emulsions, solutions, syrups, suspensions,aerosols (as a solid or in a liquid medium), and soft and hard gelatincapsules.

Examples of suitable carriers, excipients, and diluents include lactose,dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calciumphosphate, alginates, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, tragacanth, gelatin, syrup, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate,water, and mineral oil. The formulations may also include wettingagents, emulsifying and suspending agents, preserving agents, sweeteningagents or flavoring agents. The formulations of the invention may beformulated so as to provide quick, sustained, or delayed release of theactive ingredient after administration to the patient by employingprocedures well known in the art.

For oral administration, the Active Ingredient, a compound of thisinvention, may be admixed with carriers and diluents and molded intotablets or enclosed in gelatin capsules.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 1 to about 500 mg, more usually about 5 toabout 300 mg, of the Active Ingredient. The term “unit dosage form”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalcarrier.

In order to more fully illustrate the operation of this invention, thefollowing formulation examples are provided. The examples areillustrative only, and are not intended to limit the scope of theinvention. The formulations may employ as Active Ingredient any of thecompounds of the present invention.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Concentration by weight Compound Amount per capsule (mg) (%) ActiveIngredient 250 55 Starch dried 200 43 Magnesium stearate 10 2

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

Formulation 2

Capsules each containing 20 mg of medicament are made as follows:

Concentration by weight Compound Amount per capsule (mg) (%) ActiveIngredient 20 10 Starch 89 44.5 Microcrystalline 89 44.5 celluloseMagnesium stearate 2 1

The active ingredient, cellulose, starch and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve and filled into a hardgelatin capsule.

Formulation 3

Capsules each containing 100 mg of active ingredient are made asfollows:

Concentration by weight Compound Amount per capsule (mg) (%) ActiveIngredient 100 30 Polyoxyethylene  50 mcg 0.02 Sorbitan monooleateStarch powder 250 69.98

The above ingredients are thoroughly mixed and placed in an emptygelatin capsule.

Formulation 4

Tablets each containing 10 mg of active ingredient are prepared asfollows:

Amount Concentration by Compound per capsule (mg) weight (%) ActiveIngredient 10 10 Starch 45 45 Microcrystalline 35 35 cellulosePolyvinylpyrrolidone 4 4 (as 10% solution in water) Sodium carboxymethyl4.5 4.5 starch Magnesium stearate 0.5 0.5 talc 1 1

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a No. 14 mesh U.S. sieve. The granule so produced isdried at 50-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate and talc, previouslypassed through a No. 60 mesh U.S. sieve, are then added to the granules,which after mixing, is compressed on a tablet machine to yield a tabletweighing 100 mg.

Formulation 5

A tablet formula may be prepared using the ingredients below:

Compound Amount per capsule (mg) Percent by weight (%) Active Ingredient250 38 Cellulose 400 60 microcrystalline Silicon dioxide fumed 10 1.5Stearic acid 5 0.5

The components are blended and compressed to form tablets each weighing665 mg.

Formulation 6

Suspensions each containing 5 mg of medicament per 5 ml dose are made asfollows:

Amount per 5 mL Compound suspension (ml) Active Ingredient 5 Sodiumcarboxymethyl 50 cellulose Syrup 1.25 Benzoic acid solution 0.10 Flavorq.v. Color q.v. Water q.s. to 5 mL

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethylcellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor and color is diluted with some of thewater and added to the paste with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 7

An aerosol solution is prepared containing the following components:

Concentration by weight Compound (percent) Active Ingredient 0.25Ethanol 29.75 Propellant 22 70.0 (chlorodifluoromethane)

The active compound is mixed with ethanol and the mixture added to aportion of the Propellant 22, cooled to −30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted further with the remaining amount of propellant.The valve units are then fitted to the container.

Examples

Compounds of the invention may be prepared following proceduresdisclosed herein or known modifications thereof. Unless otherwiseindicated, reagents are generally available from chemical distributorsincluding those specializing in fine limited use chemicals.

Example 1 Step 1 [2-(4-Hydroxy-phenyl)-ethyl]-carbamic acid ethyl ester

Add dropwise via an addition funnel a solution of ethyl chloroformate(0.74 mL, 7.7 mmol) in tetrahydrofuran (7 mL) to a stirred solution oftyramine (1.0 g, 7.3 mmol), sodium hydroxide (0.7 g, 17.1 mmol), andwater (7 mL). Stir at room temperature for 18 hours then pour thereaction into 1N aqueous hydrochloric acid so the pH=1-2. Extract withethyl acetate (3×25 mL). Dry the combined ethyl acetate extracts oversodium chloride/magnesium sulfate, filter, and concentrate on a rotaryevaporator to yield 1.3 g, 6.2 mmol of[2-(4-hydroxy-phenyl)-ethyl]-carbamic acid ethyl ester: ¹H NMR (CDCl3,300.00 MHz): 7.01 (d, 2H); 6.78 (d, 2H); 6.26 (s, 1H); 4.78 (s, 1H);4.14-4.09 (m, 2H); 3.40-3.38 (m, 2H); 2.74-2.69 (m, 2H); 1.24-1.19 (m,3H).

Step 2 {2-[4-(4-Cyano-phenoxy)-phenyl]ethyl}-carbamic acid ethyl ester

Combine 6.2 mmol of [2-(4-hydroxy-phenyl)-ethyl]-carbamic acid ethylester (3.6.0 g, 17.2 mmol), 4-fluorobenzonitrile (2.1 g, 17.2 mmol),cesium carbonate (11.2 g, 34.4 mmol), and N,N-dimethylformamide (80 mL),stir and heat at 85° C. for 18 hours. Cool to room temperature andevaporate on a rotary evaporator, took up residue in brine thenextracted with ethyl acetate (3×50 mL). Dry the combined ethyl acetateextracts over sodium chloride/magnesium sulfate, filter, and concentrateon a rotary evaporator to yield the crude product (4.5 g). The crudeproduct is purified by flash column chromatography on silica gel elutingwith ethyl acetate and hexanes to yield{2-[4-(4-cyano-phenoxy)-phenyl]-ethyl}-carbamic acid ethyl ester (2.3g): ¹H NMR (CDCl3, 300.00 MHz): 7.66-7.60 (m, 2H), 7.31-7.24 (m, 2H),7.07-7.00 (m, 4H), 4.72 (s, 1H), 4.16 (q, 2H, J=7.0 Hz), 3.48 (q, 2H,J=6.7 Hz), 2.86 (t, 2H, J=7.0 Hz), 1.27 (t, 3H, J=7.0 Hz).

Step 3 {2-[4-(4-Acetyl-phenoxy)-phenyl]ethyl}-carbamic acid ethyl ester

1.4M methyl lithium in diethyl ether (23.2 mL, 32.5 mmol) was added viasyringe to a solution of {2-[4-(4-cyano-phenoxy)-phenyl]-ethyl}-carbamicacid ethyl ester (2.0 g, 6.5 mmol) in tetrahydrofuran (50 mL) whilestirring at −78° C. for 4 hours. Added 3M aqueous sulfuric acid (10.8mL, 32.5 mmol) to the reaction via a syringe then warm to roomtemperature for 2 hours. The reaction was allowed to stand for 72 hours,quenched with saturated aqueous sodium bicarbonate then extracted withdichloromethane (3×75 mL). The combined dichloromethane extracts weredried over sodium chloride/magnesium sulfate, filtered, and concentratedon a rotary evaporator to yield the crude product (2.1 g). The crudeproduct is purified by flash column chromatography on silica gel elutingwith ethyl acetate and hexanes to yield{2-[4-(4-acetyl-phenoxy)-phenyl]-ethyl}-carbamic acid ethyl ester (2.0g): ¹H NMR (CDCl3, 300.00 MHz): 8.0-7.9 (m, 2H), 7.25-7.15 (m, 2H),7.05-6.95 (m, 4H), 4.75 (s, 1H), 4.15 (q, 2H), 3.45 (q, 2H), 2.85 (t,2H), 2.55 (s, 3H), 1.25 (t, 3H).

Example 2 Acetic acid 4-[4-(2-ethoxycarbonylamino-ethyl)-phenoxy]-phenylester

Metachloroperbenzoic Acid (1.2 g, 4.1 mmol) was added to a solution of{2-[4-(4-acetyl-phenoxy)-phenyl]-ethyl}-carbamic acid ethyl ester (1.0g, 3.1 mmol) in chloroform (75 mL). Stirred at room temperature for 72hours, quenched with saturated aqueous Na₂S₂O₃, then extracted withdichloromethane (3×75 mL). The combined dichloromethane extracts weredried over sodium chloride/magnesium sulfate, filtered, and concentratedon a rotary evaporator to yield the crude product (2 g). The crudeproduct was purified by flash column chromatography on silica geleluting with ethyl acetate and hexanes to yield Acetic acid4-[4-(2-ethoxycarbonylamino-ethyl)-phenoxy]-phenyl ester (430 mg). ¹HNMR (CDCl3, 300.00 MHz): 7.19-6.92 (m, 8H), 4.98 (s, 1H), 4.17-4.07 (m,2H), 3.42 (q, 2H, J=6.6 Hz), 2.79 (t, 2H, J=7.2 Hz), 2.29 (s, 3H),1.30-1.20 (m, 3H), 1.30-1.20 (m, 3H), 1.30-1.20 (m, 3H).

Example 3 Step 1 4-[4-(2-Methylamino-ethyl)-phenoxy]-phenol

1.0M Lithium aluminum hydride in tetrahydrofuran (5 mL) was added to asolution of acetic acid4-[4-(2-ethoxycarbonylamino-ethyl)-phenoxy]-phenyl ester (330 mg, 1.0mmol) in tetrahydrofuran (25 mL). Refluxed overnight, cooled to roomtemperature, then quenched the reaction with saturated aqueous ammoniumchloride and stirred for 3 hours. Decanted the organic layer. Washed theremaining solid with ethyl acetate (2×30 mL). Combined all the organicwashes then concentrated on a rotary evaporator to yield4-[4-(2-Methylamino-ethyl)-phenoxy]-phenol (200 mg): HPLC=98% (5/95 to95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15cm×5 micron, λ=254 nM. ¹H NMR (CDCl3, 300.00 MHz): 7.42-6.77 (m, 8H),4.32 (s, 1H), 2.95-2.79 (m, 4H), 2.52 (s, 3H).

Step 2 4-{4-[2-(Benzyl-methyl-amino)-ethyl]-phenoxy}-phenol

Sodium triacetoxyborohydride (131 mg, 0.62 mmol) was added to a solutionof 4-[4-(2-Methylamino-ethyl)-phenoxy]-phenol (75 mg, 0.31 mmol),benzaldehyde (34 mg, 0.32 mmol), acetic acid (19 mg, 0.32 mmol), and1,2-dichloroethane (5 mL). Stirred the reaction at room temperatureovernight, quenched with a pH=10 buffer, then extracted withdichloromethane (3×25 mL). The combined dichloromethane extracts weredried over sodium chloride/magnesium sulfate, filtered, and concentratedon a rotary evaporator to yield the crude product (100 mg). The crudeproduct is purified by flash column chromatography on silica gel elutingwith ethanol in dichloromethane to yield4-{4-[2-(benzyl-methyl-amino)-ethyl]-phenoxy}-phenol, (60 mg):m/z=334.01 (M+1); HPLC=97% (5/95 to 95/5 ACN/(0.1% TFA in water) over 10minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM. ¹H NMR(CDCl3, 300.00 MHz): 7.42-7.28 (m, 7H), 7.11-7.05 (m, 2H), 6.97-6.79 (m,4H), 3.63 (s, 2H), 2.86-2.78 (m, 2H), 2.71-2.63 (m, 2H), 2.33 (s, 3H),

Example 4 Step 1 4-(2-Benzylamino-ethyl)-phenol

Combine tyramine (5 g, 36.5 mmol), benzaldehyde (9.9 g, 45.6 mmol), 3 Åmolecular sieves (10 g), and methanol (200 mL) and stir overnight atroom temperature. Cool to 5° C. then add sodium borohydride (5.5 g, 146mmol) to the reaction. Stir for 2 hours then concentrate on a rotaryevaporator. Dilute in methanol, filter, then concentrate on a rotaryevaporator. The residue was taken up in 1N hydrochloric acid and washedwith diethyl ether. The aqueous layer was basified then extracted withethyl acetate (2×100 mL. The ethyl acetate extracts were combined, driedover sodium chloride/magnesium sulfate, filtered, and concentrated on arotary evaporator to yield 4-(2-Benzylamino-ethyl)-phenol (3.3 g) ¹H NMR(CDCl3, 300.00 MHz): 9.14 (s, 1H), 7.35-7.20 (m, 5H), 7.01-6.96 (m, 2H),6.69-6.64 (m, 2H), 5.19 (s, 1H), 3.73 (s, 2H), 2.72-2.60 (m, 4H).

Step 2 4-[4-(2-B enzylamino-ethyl)-phenoxy]-benzonitrile

Reaction of 4-fluorobenzonitrile with the compound of Example 4, step 1following the procedure, of Example 1, step 2. affords the titlecompound, 4-[4-(2-Benzylamino-ethyl)-phenoxy]-benzonitrile, (2.7 g): ¹HNMR (CDCl3, 300.00 MHz): 7.65-7.58 (m, 2H), 7.41-7.25 (m, 7H), 7.06-6.98(m, 4H), 3.86 (s, 2H), 3.01-2.83 (m, 4H), m/z=328.9 (M+1).

Example 5 1-{4-[4-(2-Benzylamino-ethyl)-phenoxy]-phenyl}-ethanone

1.4M Methyl Lithium in diethyl ether was added to a dry flask thencooled to 0° C. A solution of4-[4-(2-Benzylamino-ethyl)-phenoxy]-benzonitrile (2.5 g, 7.6 mmol) (seeexample 4) in dry tetrahydrofuran (25 mL) was added dropwise to thereaction then stirred at 0° C. for 60 minutes. 3M Sulfuric Acid (12.7mL, 38 mmol) was added dropwise then the reaction was heated at 50° C.for 3 hours. The reaction was cooled to room temperature then pouredinto saturated aqueous sodium bicarbonate solution then extracted withdichloromethane (3×75 mL). The combined dichloromethane extracts weredried over sodium chloride/magnesium sulfate, filtered, and concentratedon a rotary evaporator to yield 3.1 g of crude product, which waspurified by flash column chromatography on silica gel eluting withethanol in dichloromethane to yield1-{4-[4-(2-Benzylamino-ethyl)-phenoxy]-phenyl}-ethanone (0.6 g) whichwas used directly in the next step.

Example 6 Acetic acid 4-[4-(2-benzylamino-ethyl)-phenoxy]phenyl ester

Metachloroperbenzoic acid (0.23 g) was added to a solution of1-{4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-ethanone (0.36 g) inchloroform (25 mL) while stirring at room temperature. Stirring wascontinued overnight then the reaction was diluted with dichloromethane,washed with saturated aqueous sodium thiosulfate, dried over sodiumchloride/magnesium sulfate, filtered, and concentrated on a rotaryevaporator. The residue was diluted with methanol (5 mL) and saturatedaqueous sodium bicarbonate (5 mL) then stirred overnight at roomtemperature. The methanol was removed on a rotary evaporator and the pHof the residue was adjusted to 7-8 then extracted with dichloromethane(3×30 mL). The combined dichloromethane extracts were dried over sodiumchloride/magnesium sulfate, filtered, and concentrated on a rotaryevaporator to yield 0.4 g of crude product, which was purified by flashcolumn chromatography on silica gel eluting with ethanol indichloromethane to yield Acetic acid4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl ester (117 mg), ¹H NMR(CDCl3, 300.00 MHz): 8.01-7.93 (m, 2H), 7.42-7.21 (m, 7H), 7.06-6.97 (m,4H), 3.87 (s, 2H), 3.02-2.94 (m, 4H), 2.61 (s, 3H); m/z=361.85 (M+1).

Example 7 Step 1 4-Mercapto-benzaldehyde

Combine 2-methyl-2-propanethiol sodium salt (2.9 g, 26.3 mmol) and4-(methylthio)benzaldehyde (2.0 g, 13.2 mmol) with dimethylformamide (40mL) in a dry flask then heat at 160° C. for 4 hours. Cooled to roomtemperature, poured into 3N aqueous hydrochloric acid (400 mL) thenextracted with dichloromethane (3×75 mL). The combined dichloromethaneextracts were dried over sodium chloride/magnesium sulfate, filtered,and concentrated on a rotary evaporator to yield the crude product (3g). The crude product was purified by flash column chromatography onsilica gel eluting with ethyl acetate and hexanes to yield4-mercapto-benzaldehyde (0.7 g): ¹H NMR (DMSO-D6, 300.00 MHz): 9.9 (s,1H), 7.7 (d, 2H), 7.5 (d, 2H).

Step 2 6-(4-Formyl-phenylsulfanyl)-nicotinamide

Combine 4-mercapto-benzaldehyde (0.45 g, 3.3 mmol),6-chloro-nicotinamide (0.52 g, 3.3 mmol), potassium carbonate (0.7 g,5.1 mmol), and dimethylformamide (15 mL) then heat at 70° C. overnight.Cool to room temperature, pour into water, and then extract withdichloromethane (3×75 mL). The combined dichloromethane extracts weredried over sodium chloride/magnesium sulfate, filtered, and concentratedon a rotary evaporator to yield the crude product (1 g). The crudeproduct was purified by flash column chromatography on silica geleluting with 10% aqueous ammonium hydroxide in ethanol and chloroform toyield 6-(4-formyl-phenylsulfanyl)-nicotinamide (120 mg). ¹H NMR(DMSO-D6, 300.00 MHz): 10.08 (s, 1H), 8.91 (dd, 1H, J=2.3, 0.7 Hz),8.18-8.12 (m, 2H), 8.03-7.98 (m, 2H), 7.83-7.78 (m, 2H), 7.61 (s, 1H),7.34 (dd, 1H, J=8.4, 0.8 Hz).

Step 3 6-[4-(Benzylamino-methyl)-phenylsulfanyl]-nicotinamide

Combine benzylamine (17 mg, 0.16 mmol),6-(4-formyl-phenylsulfanyl)-nicotinamide (40 mg, 0.16 mmol), 3 Åmolecular sieves (0.1 g), and methanol (3 mL) and stir overnight at roomtemperature. Filter off the sieves then add sodium borohydride (25 mg,0.64 mmol) to the reaction and stirred at room temperature for 1 hour.Pour the reaction into water then extract with ethyl acetate (3×10 mL).The combined ethyl acetate extracts were dried over sodiumchloride/magnesium sulfate, filtered, and concentrated on a rotaryevaporator to yield the crude product (50 mg). The crude product waspurified by flash column chromatography on silica gel eluting with 10%aqueous ammonium hydroxide in ethanol and chloroform to yield6-[4-(benzylamino-methyl)-phenylsulfanyl]-nicotinamide, (24 mg):m/z=349.99 (M+1); ¹H NMR (MeOD, 300.00 MHz): (8.84 (dd, 1H, J=2.3, 1.0Hz), 8.02 (dd, 1H, J=8.6, 2.3 Hz), 7.66-7.49 (m, 4H), 7.66-7.49 (m, 4H),7.42-7.34 (m, 5H), 6.99-6.92 (m, 1H), 3.88-3.77 (m, 4H). HPLC=99%@5.82minutes (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, ZorbaxSB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.By the method of Example 7 the following compounds were prepared,isolated as the free base except where noted:

Data HPLC (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, ZorbaxSB-Phenyl 4.6 mm × 15 cm × 5 micron, Mass λ = 254 nM spectrum Retention(ion spray): Time Example Name m/z (M + 1) Purity (minutes) 86-{4-[(3-Methyl- 330.04 94 5.87 butylamino)-methyl]- phenylsulfanyl}-nicotinamide 9-1 6-{4-[(2-Pyridin-4-yl- 365.00 97 5.49ethylamino)-methyl]- phenylsulfanyl}- nicotinamide 9-26-[4-(Phenethylamino- 364.02 99 5.92 methyl)-phenylsulfanyl]-nicotinamide 10 6-{4- 314.03 100 5.67 [(Cyclopropylmethyl-amino)-methyl]- phenylsulfanyl}- nicotinamide 11 6-{4-[(2-Thiophen-2-yl-369.96 100 5.67 ethylamino)-methyl]- phenylsulfanyl}- nicotinamide 126-{4-[(3-Phenyl- 378.01 99 6.01 propylamino)-methyl]- phenylsulfanyl}-nicotinamide 13 6-{4-[(3-Methyl- 330.04 99 5.85 butylamino)-methyl]-phenylsulfanyl}- nicotinamide

Example 14 4-[4-(Phenethylamino-methyl)-benzenesulfonyl]-benzamide

Add a solution of oxone (0.18 g, 0.29 mmol) in water (2 mL) was added toa solution of 4-[4-(phenethylamino-methyl)-phenylsulfanyl]-benzamide (50mg, 0.14 mmol), 1N aqueous hydrochloric acid (0.14 mL), andtetrahydrofuran (2 mL) at room temperature. Stir overnight at roomtemperature, pour into saturated aqueous sodium bisulfite, and thenextract with ethyl acetate (3×50 mL). The combined ethyl acetateextracts were washed with saturated aqueous sodium bicarbonate solution,water, and brine then dried over sodium chloride/magnesium sulfate.Filter, and concentrate on a rotary evaporator to yield 100 mg of thecrude product. The crude product is purified by flash columnchromatography on silica gel eluting with (0.2% conc. ammoniumhydroxide/2% ethanol) to (2% conc. ammonium hydroxide/20% ethanol) inchloroform to yield4-[4-(Phenethylamino-methyl)-benzenesulfonyl]-benzamide, (15 mg): ¹H NMR(DMSO-D6, 300.00 MHz): 9.06-9.01 (m, 1H), 8.50 (dd, 1H, J=8.1, 2.1 Hz),8.31 (dd, 2H, J=8.2, 0.7 Hz), 7.96-7.81 (m, 3H), 7.61 (d, 2H, J=8.2 Hz),7.32-7.15 (m, 6H), 3.88-3.82 (m, 2H), 2.78-2.71 (m, 4H); m/z=396.03(M+1); HPLC=90%@5.81 minutes (5/95 to 95/5 ACN/(0.1% TFA in water) over10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.

Example 15 4-[4-(Phenethylamino-methyl)-benzenesulfinyl]-benzamide

Sodium periodate (43 mg) was added to a solution of4-[4-(phenethylamino-methyl)-phenylsulfanyl]-benzamide (73 mg, 0.2mmol), water (10 mL), and methane sulfonic acid (39 mg, 0.4 mmol) whilestirring at room temperature. After 1 and 2 hours, and an additionalequivalent of sodium periodate (43 mg) and continue to stir at roomtemperature. Pour the reaction into saturated aqueous sodium bicarbonatesolution then extract with ethyl acetate (3×50 mL). The combined ethylacetate extracts were dried over sodium chloride/magnesium sulfate,filtered, and concentrated on a rotary evaporator to yield the crudeproduct (60 mg). The crude product was purified by flash columnchromatography on silica gel eluting with 10% aqueous ammonium hydroxidein ethanol and chloroform to yield4-[4-(Phenethylamino-methyl)-benzenesulfinyl]-benzamide (26 mg): ¹H NMR(DMSO-D6, 300.00 MHz): 8.98 (d, 1H, J=1.3 Hz), 8.46 (dd, 1H, J=7.9, 2.2Hz), 8.23 (s, 1H), 8.09 (d, 1H, J=8.3 Hz), 7.75-7.66 (m, 4H), 7.49 (d,2H, J=8.3 Hz), 7.30-7.15 (m, 5H), 3.76 (s, 2H), 2.75-2.70 (m, 4H);m/z=380.04 (M+1); HPLC=100%@5.67 minutes (5/95 to 95/5 ACN/(0.1% TFA inwater) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254nM.

Example 16 Step 1 6-(4-Cyanomethyl-phenylamino)-nicotin amide

Combine 4-aminophenylacetonitrile (5.0 g, 37.9 mmol) and6-chloro-nicotinamide (6.3 g, 40.3 mmol) in a flask and heat at 150° C.for 5 hours. Cool, dissolve the residue in methanol, dilute with ethylacetate, then wash with saturated aqueous sodium bicarbonate solution.Dry the organic layer over sodium chloride/magnesium sulfate, filtered,and concentrated on a rotary evaporator to yield the crude product (10g). The crude product was purified by flash column chromatography onsilica gel eluting with 10% aqueous ammonium hydroxide in ethanol andchloroform to yield 6-(4-cyanomethyl-phenylamino)-nicotinamide.Triturate the resulting solid with hot isopropanol, collect theprecipitate to yield 6-(4-cyanomethyl-phenylamino)-nicotinamide (1.8 g):¹H NMR (DMSO-D6, 300.00 MHz): 9.48 (s, 1H), 8.69 (d, 1H, J=2.1 Hz),8.03-7.71 (m, 4H), 7.31-7.21 (m, 3H), 6.85 (d, 1H, J=8.8 Hz), 3.97 (s,2H).

Step 2 6-[4-(2-Amino-ethyl)-phenylamino]-nicotinamide

Combine 6-(4-cyanomethyl-phenylamino)-nicotinamide (1.8 g), raney nickel(350 mg), tetrahydrofuran (50 mL), and methanol (100 mL) thenhydrogenated at 60 PSIG at 40° C. overnight. Filter off catalyst thenconcentrate on a rotary evaporator to yield6-[4-(2-amino-ethyl)-phenylamino]-nicotinamide (1.9 g).

Example 17 6-[4-(2-Benzylamino-ethyl)-phenylamino]-nicotinamide

Combine 6-[4-(2-amino-ethyl)-phenylamino]-nicotinamide (200 mg, 0.78mmol) (step 2, Example 16), benzaldehyde (83 mg, 0.78 mmol), 3 Åmolecular sieves (0.2 g), and methanol (10 mL) and stir overnight atroom temperature. Filter off the sieves then add sodium borohydride (0.4mg) to the reaction and stirred at room temperature for 4 hours. Addwater (20 mL) then extract with dicholormethane (3×50 mL). Dry thedichloromethane extracts with sodium chloride/magnesium sulfate, filter,then concentrate on a rotary evaporator to yield 0.2 g of the crudeproduct. The crude product is purified by flash column chromatography onsilica gel eluting with 10% conc. ammonium hydroxide in ethanol andchloroform to yield 6-[4-(2-Benzylamino-ethyl)-phenylamino]-nicotinamide(24 mg): ¹H NMR (MeOD, 300.00 MHz): 8.66 (d, 1H, J=1.8 Hz), 8.00 (dd,1H, J=9.0, 2.4 Hz), 7.55-7.15 (m, 10H), 6.81 (d, 1H, J=8.8 Hz), 3.80 (s,2H), 3.38 (m, 1H), 2.84 (m, 5H); m/z=347.01 (M+1); HPLC=95%@5.54 minutes(5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl4.6 mm×15 cm×5 micron, λ=254 nM.

-   -   By the method of Example 17 the following compounds were        prepared, isolated as the free base except where noted:

Data HPLC (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, ZorbaxSB-Phenyl Mass 4.6 mm × spectrum 15 cm × 5 micron, (ion λ = 254 nMspray): Retention Time Example Name m/z (M + 1) Purity (minutes) 186-{4-[2- 353.06 97 5.68 (Cyclohexylmethyl- amino)-ethyl]- phenylamino}-nicotinamide 19 6-{4-[(2-Pyridin-4- 327.05 99 5.60 yl-ethylamino)-methyl]- phenylsulfanyl}- nicotinamide

By the method of Example 15, 16, and 17 the following compounds wereprepared using 4-aminobenzonitrile as starting material:

Data HPLC (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, ZorbaxSB-Phenyl Mass 4.6 mm × 15 spectrum cm × 5 micron, (ion λ = 254 nMspray): Retention Time Example Name m/z (M + 1) Purity (minutes) 206-[4-(Benzylamino- 332.99 5.55 701 methyl)- phenylamino]- nicotinamide21 6-{4- 339.04 5.67 706 [(Cyclohexylmethyl- amino)-methyl]-phenylamino}- nicotinamide 22 6-[4- 347.02 5.66 704 (Phenethylamino-methyl)- phenylamino]- nicotinamide 23 6-{4-[(3-Methyl- 313.05 5.57 708butylamino)- methyl]- phenylamino}- nicotinamide

Example 24 Step 1 [2-(4-Hydroxy-phenyl)-ethyl]-carbamic acid tert-butylester

Combine di-tert-butyl dicarbonate (29.1 g, 133.6 mmol), tyramine (15 g,109.5 mmol), and tetrahydrofuran (750 mL) and stir at room temperaturefor 18 hours. Concentrate on a rotary evaporator to yield the crudeproduct. The crude product is purified by flash column chromatography onsilica gel eluting with 20% ethyl acetate in hexanes to yield[2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (23.5 g): ¹HNMR (CDCl3, 300.00 MHz): 7.04 (d, 2H, J=8.4 Hz), 6.82 (d, 2H, J=8.4 Hz),4.68 (s, 1H), 3.36 (d, 2H, J=5.3 Hz), 2.74 (m, 2H), 1.47 (s, 9H).

Step 2 {2-[4-(4-Nitro-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butylester

Combine [2-(4-Hydroxy-phenyl)-ethyl]carbamic acid tert-butyl ester (1.0g, 4.2 mmol), 4-fluoronitrobenzene (0.6 g, 4.2 mmol), cesium carbonate(2.7 g, 8.4 mmol), and N,N-dimethylformamide (35 mL), stir and heat at100° C. for 18 hours. Cool to room temperature and evaporate on a rotaryevaporator to yield the crude product (9.5 g). The crude product ispurified by flash column chromatography on silica gel eluting with (10%conc. ammonium hydroxide in ethanol) and chloroform to yield{2-[4-(4-nitro-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester(1.3 g): ¹H NMR (CDCl3, 300.00 MHz): 8.23 (d, 2H, J=9.2 Hz), 7.32-7.25(m, 2H), 7.10-7.00 (m, 4H), 4.63 (s, 1H), 3.43 (m, 2H), 2.86 (t, 2H,J=7.0 Hz), 1.48 (s, 9H).

Step 3 {2-[4-(4-Amino-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butylester

Combine {2-[4-(4-nitro-phenoxy)-phenyl]ethyl}-carbamic acid tert-butylester (1.3 g), 5% Pd/C (100 mg), and methanol (50 mL) then hydrogenatedat 40 PSIG at room temperature for 2 hours. Filter off catalyst thenconcentrate on a rotary evaporator to yield{2-[4-(4-Amino-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester(1.2 g): ¹H NMR (CDCl3, 300.00 MHz): 7.12 (d, 2H, J=8.4 Hz), 6.89 (d,4H, J=8.8 Hz), 6.72 (d, 2H, J=8.8 Hz), 4.61 (s, 1H), 3.42-3.32 (m, 2H),2.77 (t, 2H, J=7.0 Hz), 1.46 (s, 9H).

Step 4 {2-[4-(4-Acetylamino-phenoxy)-phenyl]-ethyl}-carbamic acidtert-butyl ester

Add a solution of {2-[4-(4-Amino-phenoxy)-phenyl]ethyl}-carbamic acidtest-butyl ester (1.2 g, 3.66 mmol) in dichloromethane (25 mL) dropwiseto a solution of acetyl chloride (0.35 g, 4.50 mmol) in dichloromethane(125 mL) at room temperature. Upon complete addition of the amine, addtriethylamine (0.74 g, 7.32 mmol) and a crystal of DMAP to the reactionand stirred at room temperature for 18 hours. Add an additional 65 uL ofacetyl chloride to the reaction and stir an additional 2 hours. Pour thereaction into saturated aqueous sodium bicarbonate then extract withdichloromethane (3×100 mL). Dry the dichloromethane extracts over sodiumchloride/magnesium sulfate, filter, then concentrate on a rotaryevaporator to yield 1.3 g of the crude product. The crude product ispurified by flash column chromatography on silica gel eluting with ethylacetate and hexanes to yield{2-[4-(4-acetylamino-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butylester (1.2 g): ¹H NMR (CDCl3, 300.00 MHz): 8.00 (s, 1H), 7.49 (d, 2H,J=8.8 Hz), 7.13 (d, 2H, J=8.4 Hz), 6.98-6.89 (m, 4H), 4.69 (s, 1H), 3.37(d, 2H, J=6.2 Hz), 2.77 (t, 2H, J=7.0 Hz), 2.18 (s, 3H), 1.46 (s, 9H).

Example 25 N-{4-[4-(2-Amino-ethyl)-phenoxy]-phenyl}-acetamide

Add trifluoroacetic acid (10 mL) dropwise to a solution of{2-[4-(4-acetylamino-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butylester (3.7 g, 10 mmol) in dichloromethane (50 mL) at 0° C. Warm to roomtemperature and stir overnight. Concentrate on a rotary evaporator,dissolve residue in methanol then apply to a strong cation exchangecolumn (Varian, 0.79 meq/g), and wash with methanol. Elute the productwith 2M ammonia in methanol then concentrate on a rotary evaporator toyield N-{4-[4-(2-amino-ethyl)-phenoxy]-phenyl}-acetamide (2.3 g): ¹H NMR(DMSO-D6, 300.00 MHz): 9.97 (s, 1H), 7.58 (d, 2H, J=8.8 Hz), 7.19 (d,2H, J=7.9 Hz), 6.92 (dd, 4H, J=21.3, 8.1 Hz), 3.60-3.05 (m, 3H),2.73-2.55 (m, 3H), 2.04 (s, 3H).

Example 26 N-{4-[4-(2-Benzylamino-ethyl)-phenoxy]-phenyl}-acetamide

Combine N-{4-[4-(2-amino-ethyl)-phenoxy]-phenyl}-acetamide (100 mg, 0.37mmol), benzaldehyde (47 mg, 0.44 mmol), 3 Å molecular sieves (300 mg),and methanol (3 mL) and stir overnight at room temperature. Filter offthe sieves then add sodium borohydride (28 mg) to the reaction andstirred at room temperature for 2 hours. Concentrate on a rotaryevaporator and purified by radial chromatography on silica gel elutingwith 10% conc. ammonium hydroxide in ethanol and chloroform to yieldN-{4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-acetamide, (61 mg): ¹HNMR (CDCl3, 300.00 MHz): 7.51-6.88 (m, 13H), 3.84 (s, 2H), 2.97-2.78 (m,4H), 2.21 (s, 3H), 1.55 (s, 1H); HPLC=99% (5/95 to 95/5 ACN/(0.1% TFA inwater) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254nM.

By the method of Example 26 the following compounds were prepared,isolated as the free base except where noted:

Data HPLC (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, ZorbaxSB-Phenyl 4.6 mm × 15 cm × 5 micron, Mass λ = 254 nM spectrum Retention(ion spray): Time Example Name m/z (M + 1) Purity (minutes) 27N-{4-[4-(2-Hexylamino- 355.16 91 ethyl)-phenoxy]-phenyl}- acetamide 28N-[4-(4-{2-[(Thiophen-2- 367.07 99 ylmethyl)-amino]-ethyl}-phenoxy)-phenyl]- acetamide 29 N-(4-{4-[2-(3-Phenyl- 389.14 97propylamino)-ethyl]- phenoxy}-phenyl)- acetamide 30 N-(4-{4-[2-(2-381.17 97 Cyclohexyl-ethylamino)- ethyl]-phenoxy}-phenyl)- acetamide 31N-{4-[4-(2- 375.12 81 Phenethylamino-ethyl)- phenoxy]-phenyl}- acetamide32 N-{4-[4-(2-Propylamino- 353.1 92 ethyl)-phenoxy]-phenyl}- acetamide33 N-{4-[4-(2-Pentylamino- 341.1 81 ethyl)-phenoxy]-phenyl}- acetamide34 N-(4-{4-[2- 367.2 97 (Cyclohexylmethyl- amino)-ethyl]-phenoxy}-phenyl)-acetamide 35 N-(4-{4-[2-(2- 429.1 92 Trifluoromethyl-benzylamino)-ethyl]- phenoxy}-phenyl)- acetamide 36N-[4-(4-{2-[(Furan-2- 351.1 95 ylmethyl)-amino]-ethyl}-phenoxy)-phenyl]- acetamide 37 N-(4-{4-[2-(3-Chloro- 395.1 98benzylamino)-ethyl]- phenoxy}-phenyl)- acetamide 38 N-{4-[4-(2- 327.1 98Isobutylamino-ethyl)- phenoxy]-phenyl}- acetamide 39 N-{4-[4-(2- 353.199 Cyclohexylamino-ethyl)- phenoxy]-phenyl}- acetamide 40N-(4-{4-[2-(2-Methyl- 375.1 99 benzylamino)-ethyl]- phenoxy}-phenyl)-acetamide 41 N-(4-{4-[2-(3-Fluoro- 379.1 87 benzylamino)-ethyl]-phenoxy}-phenyl)- acetamide 42 N-[4-(4-{2-[(3-Methyl- 381.1 99thiophen-2-ylmethyl)- amino]-ethyl}-phenoxy)- phenyl]-acetamide 43N-(4-{4-[2-(3-Methyl- 341.2 95 butylamino)-ethyl]- phenoxy}-phenyl)-acetamide 44 N-(4-{4-[2-(3,5- 397.1 86 Difluoro-benzylamino)-ethyl]-phenoxy}- phenyl)-acetamide 45 N-[4-(4-{2-[(Pyridin-3- 362.1 99ylmethyl)-amino]-ethyl}- phenoxy)-phenyl]- acetamide

Example 46 Step 1 4-(2-Benzylamino-ethyl)-phenol

Combine tyramine (3.0 g, 3.3 mmol), benzaldehyde (3.0, 2.2 mmol), 3 Åmolecular sieves (5 g), and ethanol (3 mL) and stir overnight at roomtemperature. Filter off the sieves then add sodium borohydride (2.5 g)to the reaction at 0° C. then stirred at room temperature overnight.Concentrate on a rotary evaporator, take up residue in water, and thenextract with dichloromethane (3×100 mL). Dry the dichloromethaneextracts over sodium chloride/magnesium sulfate, filter, thenconcentrate on a rotary evaporator to yield 4.3 g of the crude product.The crude product is purified by flash column chromatography on silicagel eluting with 10% cone ammonium hydroxide in ethanol and chloroformto yield 4-(2-benzylamino-ethyl)-phenol (2.6 g): ¹H NMR (DMSO-D6, 300.00MHz): 9.17 (s, 1H), 7.31 (m, 5H), 6.99 (d, 2H, J=8.4 Hz), 6.67 (d, 2H,J=8.8 Hz), 3.70 (s, 2H), 2.64 (m, 4H), 2.11 (s, 1H).

Step 2 Benzyl-[2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butylester

Combine di-tert-butyl dicarbonate (3.1 g, 14.0 mmol),4-(2-benzylamino-ethyl)-phenol (2.6 g, 11.5 mmol), and tetrahydrofuran(75 mL) and stir at room temperature for 18 hours. Concentrate on arotary evaporator to yield the crude product. The crude product ispurified by flash column chromatography on silica gel eluting with 20%ethyl acetate in hexanes to yieldbenzyl-[2-(4-hydroxy-phenyl)-ethyl]carbamic acid tert-butyl ester (2.7g): ¹H NMR (CDCl3, 300.00 MHz): 7.01-6.16 (m, 9H), 5.44 (s, 1H), 3.95(s, 2H) 2.89 (m, 2H), 2.26 (m, 2H), 1.06 (s, 9H).

Step 3 Benzyl-{2-[4-(4-nitro-phenoxy)-phenyl]-ethyl}-carbamic acidtert-butyl ester

Combine benzyl-[2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butylester (2.7 g, 8.3 mmol), 4-fluoronitrobenzene (1.2 g, 8.3 mmol), cesiumcarbonate (5.4 g, 16.6 mmol), and N,N-dimethylformamide (70 mL), stir atroom temperature overnight. Pour the reaction into brine then extractwith ethyl acetate (3×100 mL). The combined ethyl acetate extracts weredried over sodium chloride/magnesium sulfate, filtered, and concentratedon a rotary evaporator to yield the crude product (3.5 g). The crudeproduct was purified by flash column chromatography on silica geleluting with ethyl acetate and hexanes to yieldbenzyl-{2-[4-(4-nitro-phenoxy)-phenyl]ethyl}-carbamic acid tert-butylester (2.7 g): ¹H NMR (CDCl3, 300.00 MHz): 8.22 (d, 2H, J=9.2 Hz),7.44-6.95 (m, 11H), 4.44 (m, 2H), 3.44 (m, 2H), 2.84 (m, 2H), 1.52 (m,9H).

Step 4 {2-[4-(4-Amino-phenoxy)-phenyl]-ethyl}-benzyl-carbamic acidtert-butyl ester

Combine benzyl-{2-[4-(4-nitro-phenoxy)-phenyl]-ethyl}-carbamic acidtert-butyl ester (2.5 g), 5% Pd/C (200 mg), and methanol (100 mL) thenhydrogenated at 40 PSIG at room temperature for 2 hours. Filter offcatalyst then concentrate on a rotary evaporator to yield{2-[4-(4-amino-phenoxy)-phenyl]-ethyl}-benzyl-carbamic acid tert-butylester (2.3 g): ¹H NMR (CDCl3, 300.00 MHz): 7.42-6.70 (m, 13H), 4.41 (m,2H), 3.39 (m, 2H), 2.77 (m, 2H), 1.52 (s, 9H).

Step 5 4-[4-(2-B enzylamino-ethyl)-phenoxy]-phenylamine

Add trifluoroacetic acid (0.24 mL) dropwise to a solution of{2-[4-(4-Amino-phenoxy)-phenyl]-ethyl}-benzyl-carbamic acid tert-butylester (100 mg, 0.24 mmol) in dichloromethane (5 mL) at room temperatureand stir overnight. Concentrate on a rotary evaporator, dilute withsaturated aqueous sodium bicarbonate then extract with dichloromethane(3×50 mL). Dry the dichloromethane extracts over sodiumchloride/magnesium sulfate, filter, then concentrate on a rotaryevaporator to yield 4-[4-(2-benzylamino-ethyl)-phenoxy]-phenylamine, (38mg): ¹H NMR (CDCl3, 300.00 MHz): 7.42-6.67 (m, 14H), 3.86 (s, 2H), 3.61(s, 2H), 2.88 (m, 4H); m/z=319.2 (M+1); HPLC=97% (5/95 to 95/5 ACN/(0.1%TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron,λ=254 nM.

Step 6 N-{4-[4-(2-Benzylamino-ethyl)-phenoxy]-phenyl}-benzamide

Add a solution of {2-[4-(4-amino-phenoxy)-phenyl]-ethyl}-benzyl-carbamic acid tert-butyl ester (100 mg, 0.24 mmol) in dichloromethane(5 mL) dropwise to a solution of benzoyl chloride (40 mg, 0.29 mmol) indichloromethane (5 mL) at room temperature. Upon complete addition ofthe amine, add triethylamine (48 mg, 0.48 mmol) and a crystal of DMAP tothe reaction and stirred at room temperature for 18 hours. Concentrateon a rotary evaporator then purify by flash column chromatography onsilica gel eluting with ethyl acetate and hexanes to yield{2-[4-(4-benzoylamino-phenoxy)-phenyl]ethyl}-benzyl-carbamic acidtert-butyl ester (120 mg). Add trifluoroacetic acid (0.23 mL) dropwiseto a solution of[4-(4-benzoylamino-phenoxy)-phenyl]ethyl}-benzyl-carbamic acidtert-butyl ester (120 mg, 0.23 mmol) in dichloromethane (5 mL) at roomtemperature and stir overnight. Concentrate on a rotary evaporator,dilute with saturated aqueous sodium bicarbonate then extract withdichloromethane (3×50 mL). Dry the dichloromethane extracts over sodiumchloride/magnesium sulfate, filter, then concentrate on a rotaryevaporator to yieldN-{4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-benzamide, (27 mg): ¹HNMR (CDCl3, 300.00 MHz): 7.96-6.93 (m, 18H), 3.85 (s, 2H), 2.99-2.80 (m,4H), 1.56 (s, 2H); m/z=423.4 (M+1); HPLC=99% (5/95 to 95/5 ACN/(0.1% TFAin water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254nM.

By the method of Example 46 the following compounds were prepared,isolated as the free base except where noted:

Data HPLC (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, ZorbaxSB-Phenyl Mass 4.6 mm × 15 spectrum cm × 5 micron, (ion λ = 254 nMspray): Retention m/z Time Example Name (M + 1) Purity (minutes) 47Morpholine-4-carboxylic 432.5 96 acid {4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}- amide 48 N-{4-[4-(2-Benzylamino- 391.1 100ethyl)-phenoxy]-phenyl}-2- methoxy-acetamide 49 Furan-2-carboxylic acid{4- 413.1 100 [4-(2-benzylamino-ethyl)- phenoxy]-phenyl}-amide 50Isoxazole-5-carboxylic acid 414.1 80 {4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}- amide 51 Thiophene-2-carboxylic 429.1 100 acid{4-[4-(2-benzylamino- ethyl)-phenoxy]-phenyl}- amide 52N-{4-[4-(2-Benzylamino- 424.1 100 ethyl)-phenoxy]-phenyl}-isonicotinamide 53 3,5-Dimethyl-isoxazole-4- 442.1 100 carboxylic acid{4-[4-(2- benzylamino-ethyl)- phenoxy]-phenyl}-amide 542-tert-Butyl-5-methyl-2H- 483.2 99 pyrazole-3-carboxylic acid{4-[4-(2-benzylamino- ethyl)-phenoxy]-phenyl}- amide 555-Methyl-isoxazole-3- 428.1 100 carboxylic acid {4-[4-(2-benzylamino-ethyl)- phenoxy]-phenyl}-amide 56 4-Methyl- 445.1 99[1,2,3]thiadiazole-5- carboxylic acid {4-[4-(2- benzylamino-ethyl)-phenoxy]-phenyl}-amide 57 N-{4-[4-(2-Benzylamino- 421.1 100ethyl)-phenoxy]-phenyl}-3- methylsulfanyl- propionamide 58Quinoxaline-2-carboxylic 475.1 99 acid {4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}- amide 59 N-{4-[4-(2-Benzylamino- 424.4ethyl)-phenoxy]-phenyl}- nicotinamide 60 Pyridine-2-carboxylic acid424.1 99 {4-[4-(2-benzylamino- ethyl)-phenoxy]-phenyl}- amide

Example 61 Step 1 4-(5-Bromo-pyridin-2-yloxy)-benzaldehyde

To a solution of 4-hydroxy benzaldehyde (4.22 g, 34.6 mmol) and2,5-dibromopyridine (8.19 g, 34.6 mmol) in dimethylacetamide (100 mL) isadded K₂CO₃ (11.95 g, 86.4 mmol) at RT. The reaction mixture is warmedto 130° C. for 8 h. The reaction mixture is then poured into H₂O (200mL) and saturated NaHCO₃ (100 mL), extracted with EtOAc (3×200 mL), andthen the combined extracts are washed with saturated NaHCO₃, brine,dried over MgSO₄, filtered, and concentrated. The mixture is loaded onsilica gel, eluted with hexanes with a gradient from 5% of ethyl acetateto 25% of ethyl acetate giving ethyl4-(5-Bromo-pyridin-2-yloxy)-benzaldehyde (3.50 g, 36%) as a white solid.¹NMR (400 MHz, CDCl₃) δ ppm: 9.96 (s, 1H), 8.23 (d, J=2.6 Hz, 1H),7.93-7.90 (m, 2H), 7.83 (ds, J=2.6, 8.4 Hz, 1H), 7.27-7.24 (m, 2H), 6.92(d, J=7.9 Hz, 1H); MS (ES): [M+H]⁺ found 277.7.

Step 2 [4-(5-Bromo-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-amine

To a solution of 4-(5-Bromo-pyridin-2-yloxy)-benzaldehyde(RH3-A02640-038) (3.501 g, 12.6 mmol) in 1,2-dichloroethane (61 mL) isadded isoamylamine (1.65 mL, 14.2 mmol), NaBH(OAc)₃ (4.00 g, 18.9 mmol),and acetic acid (1.10 mL, 19.2 mmol). The reaction is stirred overnight.The reaction mixture is then washed with saturated NaHCO₃ (2×100 mL),dried over MgSO₄, filtered, and concentrated. The mixture is loaded onsilica gel, eluted with hexanes with a gradient from 25% of ethylacetate to 100% of ethyl acetate to give[4-(5-Bromo-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-amine (2.18 g,50%) as a yellow oil. ¹NMR (400 MHz, CDCl₃) δ ppm: 8.21 (d, J=3.1 Hz,1H), 7.75 (dd, J=2.6, 8.7 Hz, 1H), 7.37-7.34 (m, 2H), 7.09-7.05 (m, 2H),6.82 (d, J=9.1 Hz, 1H), 2.49 (s, 2H), 2.66 (dd, J=7.6, 7.6 Hz, 2H),1.67-1.61 (m, 1H), 1.44-1.38 (m, 2H), 1.15 (s br, 1H), 0.90 (d, J=6.6Hz, 6H); MS (ES): [M+H]⁺ found 261.7.

Step 3N-(6-{4-[(3-Methyl-butylamino)-methyl]-phenoxy}-pyridin-3-yl)-acetamide

To a solution of[4-(5-Bromo-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-amine (0.493 g,1.411 mmol), acetamide (0.0938 g, 1.588 mmol), and CuI (0.0309 g, 1.622mmol) in 1,4-dioxane (3.0 ml) is added(+/−)-trans-1,2-diaminocyclohexane (0.020 mL, 1.67 mmol) and K₂CO₃(0.400 g, 0.891 mmol). The reaction mixture is then warmed to 100° C.overnight. Additional amounts of CO (0.0270 mg, 0.142 mmol) and(+/−)-trans-1,2-diaminocyclohexane (0.020 mL, 1.67 mmol) are added. Thereaction mixture is placed in a microwave reactor (CEM Discover, 50 W)for 60 min. The mixture is filtered through celite, loaded onto silicagel, and eluted with chloroform with a gradient from 10% of methanol to30% of methanol to giveN-(6-{4-[(3-Methyl-butylamino)-methyl]-phenoxy}-pyridin-3-yl)-acetamide(0.025 g, 5%) as a brown oil. ¹NMR (400 MHz, CD₃OD) δ ppm: 8.30 (d,J=2.7 Hz, 1H), 8.04 (dd, J=2.5, 8.7 Hz, 1H), 7.38 (d, J=8.6 Hz, 2H),7.07-7.03 (m, 2H), 6.91 (d, J=8.9 Hz, 1H), 3.82 (s, 2H), 2.68 (dd,J=7.7, 8.0 Hz, 2H), 2.18 (s, 3H), 1.70-1.61 (m, 1H), 1.52-1.44 (m, 2H),0.96 (d, J=6.6 Hz, 6H); MS (ES): [M+H]⁺ calcd for C₁₉H₂₆N₃O₂=328.2025,found 328.2000

Example 62 4-[4-(2-Benzylaminoethyl)phenoxy]benzenesulfonamide

Part A: 4-Fluorobenzenesulfonyl azide

Suspend 4-fluorobenzenesulfonyl chloride (0.500 g, 2.57 mmol) and sodiumazide (0.200 g, 3.08 mmol) in acetone. Heat at reflux overnight beforeconcentrating the reaction mixture. Purify by flash 40 chromatography,eluting with 10% ethyl acetate in hexanes to give the title compound:¹HNMR (DMSO-d₆) δ 7.58 (tt, J=8.04, 2.02 Hz, 2H), 8.12 (td, 4.89, 1.96Hz, 2H); HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrilein water containing 0.01% concentrated HCl at 1.0 mL/min, 50-99% over 19min], t_(R)=16.5 min, 92.4% purity.

Part B: {2-[4-(4-Azidosulfonylphenoxy)phenyl]ethyl}carbamic acidtert-butyl ester

Dissolve [2-(4-hydroxyphenyl)ethyl]carbamic acid tert-butyl ester (0.594g, 2.50 mmol) in DMF (12.5 mL). Add NaH (80% in mineral oil) (0.083 g,2.75 mmol). Stir at room temperature for 30 minutes. Add4-fluorobenzenesulfonyl azide (0.504 g, 2.50 mmol) and heat to 60° C.Remove DMF as an azeotrope with xylenes after 3.75 hours. Purify byflash 40 chromatography, eluting with 30% ethyl acetate in hexanes togive a mixture of(2-(4-(4-fluorobenzenesulfonyl)oxyphenyl)ethyl)carbamic acid tert-butylester and the title compound: HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0mL/min, 50-99% over 19 min], t_(R)=16.1 min, 35% purity; TLC [silica gel60 F₂₅₄, 5% ethyl acetate in hexanes] R_(f)=0.49.

Part C: 4-[4-(2-Aminoethyl)phenoxy]benzenesulfonyl azide

Dissolve the mixture of{2-[4-(4-azidosulfonylphenoxy)phenyl]ethyl}carbamic acid tert-butylester (0.291 g, 0.695 mmol) in dichloromethane (12 mL). Add TFA (12 mL)and stir at room temperature for 5 hours. Concentrate the reactionmixture. Load the product onto an SCX column with methanol. Wash thecolumn with methanol then elute with 50% (2.0 M NH₃ in methanol) inmethanol to give a mixture of2-4-(4-fluorobenzenesulfonyl)oxyphenyl)ethylamine and the title compound(0.601 g, 98.5%): MS ES⁺ 336.9 (M+H+18(NH₄))⁺; TLC [silica gel 60 F₂₅₄,30% ethyl acetate, 5% (2.0 M NH₃ in methanol and 65% hexanes]R_(f)=0.034.

Part D: 4-[4-(2-Benzylaminoethyl)phenoxy]benzenesulfonamide

Take up the mixture of 4-[4-(2-aminoethyl)phenoxy]benzenesulfonyl azide(0.210 g, 0.661 mmol) in methanol (9.9 mL). Add benzaldehyde (0.20 mL,1.98 mmol) and 3 Å molecular sieves. Stir at room temperature overnight.Add NaBH₄ (0.075 g, 1.98 mmol) and stir for 1.5 hours. Filter thereaction mixture and purify by flash 40 chromatography, eluting with 3%(2.0 M NH₃ in methanol), 30% hexanes and 67% ethyl acetate to give thetitle compound (0.0696 g, 25.8%): TOF MS ES⁺ 383.1 (M+H)⁺, HRMS calcdfor C₂₁H₂₃N₂O₃S 383.1429 (M+H)⁺, found 383.1436, time 0.33 min; TLC[silica gel 60 F₂₅₄, 10% (2.0 M NH₃ in methanol) in dichloromethane]R_(f)=0.31.

Example 63 6-(4-Cyano-benzyl)-nicotinamide Step 1

Following the procedure disclosed in J. Het. Chem. 1999, 36, 445, asolution of 4-cyanobenzyl bromide (1 g, 5.1 mmol) in THF (5 mL) is addedto a stirred suspension of Zinc dust (498 mg, 7.5 mmol) in anhydrous THF(7 mL) cooled in an ice bath under a nitrogen atmosphere. The suspensionwas stirred for 5 hours in an ice bath. In a separate flask, anhydrousTHF (26 mL) is added to dichloro-bis-(triphenylphosphine) Nickel II (560mg, 0.86 mmol) under nitrogen atmosphere at room temperature.6-chloro-nicotinamide (800 mg, 5.1 mmol) in THF (20 mL) is added to thecatalyst; not all material is in solution. After stirring 5 minutes, thezinc dust suspension is allowed to settle, and the solution is added viacannula to the nickel catalyst/nicotinamide mixture, taking care toleave unreacted zinc dust behind. The reaction immediately turns darkpurple, and is stirred for 72 hours at room temperature under nitrogen,at which point the reaction is a clear yellow solution. A saturatedaqueous solution of ammonium chloride; (50 mL) is added and the mixturestirred 20 minutes. The reaction mixture is then washed with 3×50 mLethyl acetate, and the organics washed with 2×50 mL brine, dried overmagnesium sulfate, and evaporated to give a tan solid. The solid iswashed with ether, and the ether layer discarded. The remaining materialwas dried under vacuum to give 723 mg crude material. The material ispurified by flash chromatography on an ISCO (dry pack onto 12 g column;gradient: 40 mL/min, EtOAc 0-15 min, 0-5% MeOH/EtOAc 15-30 min, 5%MeOH/EtOAc 30-35 min). Product is isolated as a whit solid, 110 mg, plusan additional 225 mg product contaminated with starting material. Thisis re-purified as above to give an additional 67 mg product. Total yield177 mg (15%).

¹H NMR (CD₃OD): 8.94 (d, 1H, J=3 Hz); 8.20 (dd, 1H, J=7 Hz, 19 Hz); 7.66(d, 2H, J=19 Hz); 7.45 (m, 3H); 4.28 (s, 2H)

Step 2 6-(4-Formyl-benzyl)-nicotinamide

Compound 1 (175 mg) is dissolved in anhydrous THF (15 mL) and cooled toin a dry ice/acetone bath. A 1M solution of DIBAl-H in toluene (1 mL) isadded and the reaction is stirred for 1 hour at −78°. After 1 hour, anadditional 1 mL DIBAL-H solution is added, and the reaction is placed at−28° overnight. The reaction is then warmed to room temperature, stirredfor 3 hours, and treated with an additional 700 uL DIBAL-H solution, atwhich point no starting nitrile remains. Water is added (25 mL) and themixture is stirred 5 minutes, then extracted with 3×50 mL ethyl acetate.The organics are washed with 50 mL brine, dried over magnesium sulfate,and evaporated to yield 144 mg crude product. This is purified by flashchromatography on an ISCO (10 g column, 40 mL/min, gradient: EtOAc, 0-10min; 0-5% MeOH/EtOAc 10-25 minutes) to give 47 mg final product (27%yield).

¹H NMR (CD₃OD): 9.94 (s, 1H); 9.5 (s, 1H); 8.20 (dd, 1H, J=6 Hz, 20 Hz);7.85 (d, 2H, J=20 Hz); 7.46 (m, 3H); 4.30 (s, 2H).

MS: 241.0 (M+1)

Step 3 6-{4-[(3-Methyl-butylamino)-methyl]-benzyl}-nicotinamide

A mixture of aldehyde 2 (22 mg, 90 umol) is dispersed in methanol (2mL). To this mixture is added 2-methylbutylamine (15 mg, 170 umol); allsolid dissolves after 10 minutes of stirring at room temperature. To thestirred solution is added sodium borohydride (14 mg, 370 umol),significant gas evolution is observed. The reaction mixture is thenpoured onto a 1 g Varian SCX cartridge which has been conditioned with a5% solution of acetic acid in methanol. The column is rinsed withmethanol, then eluted using 2.5 mL of a 2N ammonia solution in methanol,and the organic is evaporated to give 30 mg crude material. This ispurified by flash chromatography using an ISCO (4 g column, eluent: 40mL/min, 1-5% (1N NH₃/MeOH)/CH₂Cl₂, 0-10 min; 5% (1N NH₃/MeOH)/CH₂Cl₂,10-15 min, 5-10% (1N NH₃/MeOH)/CH₂Cl₂, 15-20 minutes) to give 21 mgclean product (75% yield).

1H NMR (CDCl₃): 8.93 (s, 1H); 8.03 (dd, 1H, J=6 Hz, 20 Hz); 7.26 (m,5H); 6.1 (br s, 1H); 5.8 (br s, 1H); 4.19 (s, 2H); 3.75 (s, 2H); 2.62(t, 2H, J=19 Hz); 1.60 (m, 1H); 1.40 (m, 2H); 0.90 (m, 6H).

MS: 312 (M+1).

1. A compound selected from the group6-[4-(2-Benzylamino-ethyl)-phenylamino]-nicotinamide,6-{4-[2-(Cyclohexylmethyl-amino)-ethyl]-phenylamino}-nicotinamide,6-[4-(Benzylamino-methyl)-phenylamino]-nicotinamide,6-{4-[(Cyclohexylmethyl-amino)-methyl]-phenylamino}-nicotinamide,6-[4-(Phenethylamino-methyl)-phenylamino]-nicotinamide,6-{4-[(3-Methyl-butylamino)-methyl]-phenylamino}-nicotinamide, or apharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a compound according to claim 1 in associationwith a carrier, diluent and/or excipient.
 3. A compound6-[4-(2-Amino-ethyl)-phenylamino]-nicotinamide, or a pharmaceuticallyacceptable salt thereof.
 4. A pharmaceutical composition comprising acompound according to claim 3 in association with a carrier, diluentand/or excipient.